EP1718594A1 - Compositions, procedes et agents eclaircissant la peau - Google Patents

Compositions, procedes et agents eclaircissant la peau

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Publication number
EP1718594A1
EP1718594A1 EP05715365A EP05715365A EP1718594A1 EP 1718594 A1 EP1718594 A1 EP 1718594A1 EP 05715365 A EP05715365 A EP 05715365A EP 05715365 A EP05715365 A EP 05715365A EP 1718594 A1 EP1718594 A1 EP 1718594A1
Authority
EP
European Patent Office
Prior art keywords
compound
daim
alkyl
saturated
unsaturated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP05715365A
Other languages
German (de)
English (en)
Other versions
EP1718594B1 (fr
Inventor
Bijan Harichian
Jose Guillermo Rosa
Michael James Barratt
Carol Annette Bosko
John Steven Bajor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Unilever PLC
Unilever NV
Original Assignee
Unilever PLC
Unilever NV
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Publication of EP1718594A1 publication Critical patent/EP1718594A1/fr
Application granted granted Critical
Publication of EP1718594B1 publication Critical patent/EP1718594B1/fr
Active legal-status Critical Current
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

Definitions

  • the invention relates to coumarin derived compounds and cosmetic compositions including same, and more specifically, to 4-substituted 7-hydroxy coumarin derived compounds, and their cosmetic use, for example, as skin lightening agents.
  • Resorcinol derivatives have cosmetic skin and hair benefits. Certain resor ⁇ ' nol derivatives, particularly 4-substituted resorcinol derivatives, are useful in cosmetic compositions for skin lightening benefits. Resorcinol derivatives are described in many publications, including Torihara etal., U.S. Patent No.4,959,393; Hu et al., U.S. Patent No. 6,132,740; Bradley, et al., U.S. Patent No. 6,504,037; and Japanese published patent applications JP 2001- 010925 and JP2000-327557.
  • Resorcinol derivatives are known compounds and can be readily obtained by various means, including by a method wherein a saturated carboxylic acid and resorcinol are condensed in the presence of zinc chloride and the resultant condensate is reduced with zinc amalgam/hydrochloric acid (Lille, et al., Tr. Nauch-lssled. Inst. Slantsev 1969, No. 18:127-134), or by a method wherein resorcinol and a corresponding alkyl alcohol are reacted in the presence of an alumina catalyst at a high temperature of from 200 to 400 ° C (British Patent No. 1 ,581,428).
  • Skin lightening compounds that may be derived from coumarin are disclosed in U.S. Patent Publication No. 2004/0042983. Some of these compounds can be irritating to the skin.
  • compositions including same deliver cosmetic benefits, particularly skin lightening benefits, with potentially reduced irritation and relative ease of manufacture.
  • the present invention provides a cosmetic method of skin lightening using a composition comprising in addition to a cosmetically acceptable vehicle, 0.000001 to 50% by weight of the composition, of a compound of formula I, (I)
  • each or both Ri and/or R 2 represents hydrogen (H); linear or branched, saturated or unsaturated, Ci - C ⁇ 2 alkyl, alkenyl, acyl, or heteroalkyl (e.g., preferably, alkoxy) groups.
  • each or both Ri and/or R 2 represents hydrogen (H); linear or branched, saturated or unsaturated, Ci - C ⁇ 2 alkyl or acyl groups. More preferably, both Ri and R 2 represent hydrogen; and
  • R3 represents linear or branched, cyclic or acyclic, saturated or unsaturated Ci - d 2 alkyl, alkenyl, cycloalkyl, cycloalkenyl, or heteroalkyl group.
  • R3 represents an alkyl group. More preferably, R3 represents a Ci alkyl group (i.e, methyl group); and
  • R 5 represents a hydrogen atom (H) or R*.
  • R5 represents H.
  • P represents linear or branched, cyclic or acyclic, saturated or unsaturated, containing or not containing a heteroatom (e.g. furans, dihydrofurans, pyrans), d- C 22 alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl, aryl, or heteroaryl group.
  • R represents linear or branched, cyclic or acyclic, saturated or unsaturated, C1-C22 alkyl group.
  • each Ri, R 2 and R5 represent H, while R3 represents a methyl group, i.e. compound of formula II herein.
  • These 4-methyl 7-hydroxy coumarin derived compounds, or coumarin derived resorcinol derivatives, may be prepared by catalytic (nickel or paladium catalyst) hydrogenation of 4-substituted 7-hydroxy-coumarin followed by hydrolysis.
  • the hydroxy groups (where any of Ri, R 2 and R5 represents H) may be further substituted by methods known in the art, such as by esterification.
  • the invention provides a process for making compounds having a general formula selected from the group consisting of B, C, D, and mixtures thereof, comprising:
  • R 3 represents linear or branched, cyclic or acyclic, saturated or unsaturated Ci - C- ⁇ 2 alkyl, alkenyl, cycloalkyl, cycloalkenyl, or heteroalkyl group;
  • R 4 represents linear or branched, cyclic or acyclic, saturated or unsaturated, containing or not containing a heteroatom, C1-C22 alkyl, alkenyl, cycloalkyl, cycloalkenyl, heteroalkyl, aryl, or heteroaryl group.
  • the process may further comprise substitution of the 1 ,3-hydroxy positions of the phenyl ring to yield a compound of general formula I: (I)
  • each or both Ri and/or R 2 represents hydrogen (H); linear or branched, saturated or unsaturated Ci - C 12 alkyl, alkenyl, acyl, or heteroalkyl groups.
  • compositions such as alpha- hydroxy acids, beta-hydroxy acids, polyhydroxy acids, hydroquinone, t-butyl hydroquinone, Vitamin C derivatives, dioic acids, retinoids, resorcinol derivatives, and mixtures thereof.
  • Organic and inorganic sunscreens may also be included.
  • the use of the compounds, which may be derived from (although not limited to being derived from) coumarin derivatives delivers skin lightening benefits.
  • the general chemical formulas and structures of these compounds are discussed in more detail herein below.
  • the 4-substituted 7-hydroxy coumarin derived compounds have been found to be effective cosmetic agents, particularly, skin lightening agents, and are relatively simple to produce.
  • composition is intended to describe compositions for topical application to human skin.
  • skin as used herein includes the skin on the face, neck, chest, back, arms, axilla, hands, legs, and scalp.
  • the invention is concerned with compounds of general formula I, compositions including same, and their cosmetic use, particularly as skin lightening agents.
  • a particular advantage of the compositions and methods is that compounds of general formula I can be less irritating to the skin than other skin lightening compounds, even those with similar structure, and are relatively easy to manufacture.
  • This most preferred embodiment referred to herein as a 4-methyl 7-hydroxy coumarin derived compound, or coumarin derived resorcinol derivative, may be prepared by catalytic (nickel or paladium catalyst, preferably Pd on carbon substrate, i.e., Pd/C) hydrogenation of 4-methyl 7-hydroxy coumarin followed by hydrolysis.
  • catalytic nickel or paladium catalyst, preferably Pd on carbon substrate, i.e., Pd/C
  • the hydroxy groups may be further substituted by methods known in the art, such as by esterification. Other methods of deriving the compounds may also be available and the invention is not limited by the method of preparation.
  • compositions generally contain 0.000001 to 50% by weight of the composition of coumarin derived compounds of general formula I.
  • Compounds of formula II are preferred.
  • the amount of the coumarin derived compounds is preferably in the range of 0.00001 % to 10% by weight, more preferably 0.001 to 7% by weight, most preferably from 0.01 to 5% by weight, of the total amount of a cosmetic composition.
  • compositions useful for the method may be included in the compositions useful for the method.
  • Organic and inorganic sunscreens may also be included.
  • a high pressure reaction vessel is charged with compound of general formula A, a 4- substituted-7-hydroxy coumarin (preferably, 4-alkyl-7-hydroxy coumarin), in a suitable solvent (e.g., acetic acid, alcohol, organic solvents and mixtures thereof) and a catalyst is added (e.g., homogeneous or heterogeneous catalysts such as Pd and/or Ni attached to a suitable matrix and mixtures thereof).
  • a suitable solvent e.g., acetic acid, alcohol, organic solvents and mixtures thereof
  • a catalyst e.g., homogeneous or heterogeneous catalysts such as Pd and/or Ni attached to a suitable matrix and mixtures thereof.
  • the reactor is pressurized with hydrogen (e.g., 690 kPa to 5.5 MPa [100 to 800 psi]) and stirred above 25°C (e.g., 25°C to 60°C) until complete consumption of 4-substituted-7-hydroxy coumarin (preferably, 4-alkyl-7-hydroxy coumarin) is observed as monitored using a suitable analytical method (e.g., TLC, GC, LC, hydrogen consumption, and combinations thereof)-
  • a suitable analytical method e.g., TLC, GC, LC, hydrogen consumption, and combinations thereof
  • the reaction mixture is filtered through an insoluble support (e.g., CeliteTM, silica gel, and combinations thereof), the solvents removed under reduced pressure and the product purified using purification methods such as, for example, re-crystallization, distillation, and combinations thereof.
  • a Parr hydrogenator (1 L) was charged with 7-hydroxy-4-methyl coumarin, i.e., compound of formula A1 , (60 g, 0.34 mol) and acetic add (350 ml).
  • a suspension of 10% Pd/C (6.0 g) in acetic add (150 ml) was added and the reactor sealed, evacuated and purged with nitrogen (4X).
  • the reactor was pressurized to 2.2 MPa (320 psi) with hydrogen and stirred at 30 °C for 16 hr, at which point no hydrogen was consumed and TLC (4% methanol:chloroform) showed the dean formation of product at the expense of starting material.
  • the reactor was evacuated, purged with nitrogen and the mixture filtered through CeliteTM.
  • reaction A compound of general formula B i.e., 4-substituted-3,4-dihydro-7-hydroxycoumarin, is suspended in water and a hydroxide ion equivalent reagent is added (e.g., sodium hydroxide, potassium hydroxide, polymer-bound carbonate, and combinations thereof).
  • a hydroxide ion equivalent reagent e.g., sodium hydroxide, potassium hydroxide, polymer-bound carbonate, and combinations thereof.
  • the reaction is monitored using a suitable analytical method (e.g., TLC, GC, LC, and combinations thereof) until complete consumption of the starting material.
  • the reaction0 mixture is cooled down (e.g., temperatures between 0 and 10°C) and addified with a hydrogen ion equivalent reagent (e.g., hydrochloric add) until the pH of the solution reaches 1 or below.
  • a hydrogen ion equivalent reagent e.g., hydrochloric add
  • the solution is extracted with a suitable organic solvent (e.g., diethyl ether), the organic layer dried using an insoluble drying agent (e.g., sodium sulfate), filtered and the solvent removed.
  • a suitable organic solvent e.g., diethyl ether
  • an insoluble drying agent e.g., sodium sulfate
  • the product is purified using purification methods such as, for5 example, re-crystallization, distillation, chromatography, or combination thereof.
  • a compound of general formula B i.e., 4-substituted-3,4-dihydro-7-hydroxy coumarin, is dissolved in the alcohol of choice or, alternately, the coumarin and the alcohol are dissolved in a suitable solvent (e.g., tetrahydrofuran).
  • An acid catalyst is added (e.g., sulfuric acid, acidic resin, or combinations thereof) and the reaction is monitored using a suitable analytical method (e.g., TLC, GC, LC, or combinations thereof) until complete consumption of the starting material.
  • the reaction mixture is partly neutralized (to pH of 4 to 7) with mild base (e.g., aqueous sodium bicarbonate) and partitioned between a suitable organic solvent
  • the organic layer is dried using an insoluble drying agent (e.g., sodium sulfate), filtered and the solvent removed under reduced pressure.
  • the product is purified using purification methods such as, for example, re-crystallization, distillation, chromatography, and/or combinations thereof.
  • Preferred cosmetic compositions are those suitable for the application to human skin according to the method of the present invention, which optionally, but preferably, indude a skin benefit agent in addition to the coumarin derived compounds.
  • Suitable additional skin benefit agents indude anti-aging, wrinkle-redudng, skin whitening, anti-acne, and sebum reduction agents. Examples of these indude alpha-hydroxy adds, beta-hydroxy adds, polyhydroxy adds, hydroquinone, t-butyl hydroquinone, Vitamic C derivatives, dioic acids, retinoids; betulinic add; allantoin, a placenta extract; and other resordnol derivatives.
  • the cosmetically acceptable vehicle may act as a dilutant, dispersant or carrier for the skin benefit ingredients in the composition, so as to facilitate their distribution when the composition is applied to the skin.
  • the vehicle may be aqueous, anhydrous or an emulsion.
  • the compositions are aqueous or an emulsion, especially water-in-oil or oil-in-water emulsion, preferentially oil-in-water emulsion.
  • Water when present will be in amounts which may range from 5 to 99%, preferably from 20 to 70%, optimally between 40 and 70% by weight of the cosmetic composition.
  • relatively volatile solvents may also serve as carriers within compositions of the present invention.
  • monohydric CrC 3 alkanols include ethyl alcohol, methyl alcohol and isopropyl alcohol.
  • the amount of monohydric alkanol may range from 1 to 70%, preferably from 10 to 50%, optimally between 15 to 40% by weight of the cosmetic composition.
  • Emollient materials may also serve as cosmetically acceptable carriers. These may be in the form of silicone oils and synthetic esters. Amounts of the emollients may range anywhere from 0.1 to 50%, preferably between 1 and 20% by weight of the cosmetic composition.
  • Silicone oils may be divided into the volatile and non-volatile variety. The term
  • volatile refers to those materials which have a measurable vapor pressure at ambient temperature.
  • Volatile silicone oils are preferably chosen from cyclic or linear polydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5, silicon atoms.
  • Linear volatile silicone materials generally have viscosities less than 5 centistokes (5 x 10 "6 m 2 s “1 ) at 25°C while cyclic materials typically have viscosities of less than 10 centistokes (1 x 10 "5 m 2 s "1 ).
  • Non-volatile silicone oils useful as an emollient material include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers.
  • the essentially non-volatile polyalkyl siloxanes useful herein include, for example, polydimethyl siloxanes with viscosities of from 5 to 25 million centistokes (5 x 10 "6 m 2 s “1 to 25 m 2 s “1 ) at 25°C.
  • polydimethyl siloxanes having viscosities from 10 to 400 centistokes (1 x 10 "5 m 2 s “1 to 4 x 10 "4 m 2 s "1 ) at 25°C.
  • ester emollients are:
  • Alkenyl or alkyl esters of fatty acids having 10 to 20 carbon atoms examples thereof include isoarachidyl neopentanoate, isononyl isonanonoate, oleyl myristate, oleyl stearate, and oleyl oleate.
  • Ether-esters such as fatty acid esters of ethoxylated fatty alcohols.
  • Polyhydric alcohol esters Ethylene glycol mono and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty esters, ethoxylated glyceryl monostearate, 1 ,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters.
  • Wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate and arachidyl behenate.
  • Sterol esters of which cholesterol fatty acid esters are examples.
  • Fatty acids having from 10 to 30 carbon atoms may also be included as cosmetically acceptable carriers for compositions of this invention.
  • Illustrative of this category are pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic and erucic acids.
  • Humectants of the polyhydric alcohol-type may also be employed as cosmetically acceptable carriers in compositions of this invention.
  • the humectant aids in increasing the effectiveness of the emollient, reduces scaling, stimulates removal of built-up scale and improves skin feel.
  • Typical polyhydric alcohols include glycerol, polyalkylene glycols and more preferably alkylene polyols and their derivatives, including propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1 ,3-butylene glycol, 1 ,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof.
  • the humectant is preferably propylene glycol or sodium hyaluronate.
  • the amount of humectant may range anywhere from 0.5 to 30%, preferably between 1 and 15% by weight of the cosmetic composition.
  • Thickeners may also be utilized as part of the cosmetically acceptable carrier of compositions according to the present invention.
  • Typical thickeners include crosslinked acrylates (e.g. Carbopol 982), hydrophobically-modified acrylates (e.g. Carbopol 1382), cellulosic derivatives and natural gums.
  • useful cellulosic derivatives are sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose and hydroxymethyl cellulose.
  • Natural gums suitable for the present invention include guar, xanthan, sclerotium, carrageenan, pectin and combinations of these gums.
  • Amounts of the thickener may range from 0.0001 to 5%, usually from 0.001 to 1 %, optimally from 0.01 to 0.5% by weight of the cosmetic composition.
  • the water, solvents, silicones, esters, fatty acids, humectants and/or thickeners will constitute the cosmetically acceptable carrier in amounts from 1 to 99.9%, preferably from 80 to 99% by weight of the cosmetic composition.
  • An oil or oily material may be present, together with an emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the average hydrophilic-lipophilic balance (HLB) of the emulsifier employed.
  • HLB hydrophilic-lipophilic balance
  • Surfactants may also be present in cosmetic compositions of the present invention. Total concentration of the surfactant will range from 0.1 to 40%, preferably from 1 to 20%, optimally from 1 to 5% by weight of the composition.
  • the surfactant may be selected from the group consisting of anionic, nonionic, cationic and amphoteric actives.
  • nonionic surfactants are those with a C ⁇ o-C 2 o fatty alcohol or acid hydrophobe condensed with from 2 to 100 moles of ethylene oxide or propylene oxide per mole of hydrophobe; C 2 -C ⁇ o alkyl phenols condensed with from 2 to 20 moles of alkylene oxide; mono- and di- fatty acid esters of ethylene glycol; fatty acid monoglyceride; sorbitan, mono- and di- C ⁇ -C 2 o fatty acids; block copolymers (ethylene oxide/propylene oxide); and polyoxyethylene sorbitan as well as combinations thereof.
  • Alkyl polyglycosides and saccharide fatty amides are also suitable nonionic surfactants.
  • Preferred anionic surfactants include soap, alkyl ether sulfate and sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates, alkyl and dialkyl sulfosucci nates, C 8 -C 20 acyl isethionates, acyl glutamates, C ⁇ -C 2 o alkyl ether phosphates and combinations thereof.
  • plasticizers there may be optionally added plasticizers; calamine; antioxidants; chelating agents; as well as sunscreens.
  • Other adjunct minor components may also be incorporated into the cosmetic compositions. These ingredients may indude coloring agents, pigments, opadfiers, and perfumes. Amounts of these other adjunct minor components may range anywhere from 0.001 % up to 20% by weight of the composition.
  • Sunscreens For use as sunscreen, metal oxides may be used alone or in mixture and/or in combination with organic sunscreens. Examples of organic sunscreens include but are not limited those set forth in the table below.
  • the amount of the organic suns ⁇ eens in the cosmetic composition is preferably in the range of 0.1 wt % to 10 wt %, more preferably 1 wt % to 5 wt %.
  • Preferred organic sunscreens are PARSOLTM MCX and PARSOLTM 1789, due to their effectiveness and commercial availability. USE OF THE COMPOSITION
  • the method according to the invention is intended primarily as use of a personal care product for topical application to human skin to lighten the skin, to reduce the degree of pigmentation in the skin, and/or to even the skin tone.
  • a small quantity of the composition for example from 1 to 5 ml, is applied to exposed areas of the skin, from a suitable container or applicator and, if necessary, it is then spread over and/or rubbed into the skin using the hand or fingers or a suitable device.
  • the cosmetic composition of the invention can be formulated as a lotion having a viscosity (at 20°C) of from 4,000 to 10,000 mPas, a fluid cream having a viscosity (at 20°C) of from 10,000 to 20, 000 mPas, or a cream having a viscosity (at 20°C) of from 20,000 to 100,000 mPas or above.
  • the composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer.
  • a lotion or fluid cream can be packaged in a bottle or a roll-ball applicator or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation.
  • composition When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar. When the composition is a solid or semi-solid stick, it may be packaged in a suitable container for manually or mechanically pushing out or extruding the composition.
  • the invention accordingly also provides a dosed container containing a cosmetically acceptable composition as herein defined.
  • the compound of formula A1 referred to herein as 4-methyl 7-hydroxy coumarin was used as a starting material to prepare the coumarin derived resorcinol compounds according to the present invention, as follows:
  • phase A ingredients were heated in a separate container to 70 to 85°C with stirring.
  • phase B ingredients were heated in a separate container to 70 to 85°C with stirring.
  • phase A was added into phase B while both phases were kept at 70 to 85°C.
  • the mixture was stirred for at least 15 minutes at 70 to 85°C, and then cooled.
  • Example 3 The composition of Example 3, was prepared as follows: 1. Heat Phase A to 80°C 2. Heat Phase B to 75°C in a separate container 3. Add B to A and mix with heat off for 30 min. 4. At 50°C add Phase C and mix for 10 min.
  • compositions useful in the methods of the present invention were prepared within the scope of the present invention and are listed in the table below.
  • the compositions were prepared using the method described in Example 3.
  • EXAMPLE 12 Cell Based Assay This example shows the skin lightening effect of using 4-methyl 7-hydroxy coumarin derived resorcinol compounds as skin lightening agents in accordance with the method. This experiment was carried out using a cell based assay.
  • B16 mouse melanoma cells were utilized in the following experiment to evaluate the efficacy of skin lightening agents.
  • B16 cells were plated in 96-well microtiter plates at a density of 5000 cells per well and cultured overnight in Dulbecco's Modified Eagle's Medium (phenol red free) containing 10% fetal bovine serum and 1% penidllin/streptomydn at 37°C in the presence of 5% C0 2 . After 24 hours, the medium was replaced with fresh growth medium containing the treatments. All cultures were incubated for 72 hours at which time melanin was visible in the control treatment. The melanin-containing medium was transferred to a dean 96-well plate and quantified by reading the absorbency at 530 nm. Cell viability was assessed by measurement of lactate dehydrogenase levels to ensure the decrease in melanin was not a result of cellular toxidty.
  • Mushroom tyrosinase inhibition is indicative of reduction in melanin synthesis, thereby showing skin lightening effect.
  • This experiment shows the efficacy of 5 coumarin derived resorcinol derivatives of the present invention.
  • Absorbency was read at 475 nm over the following time points: 0, 2, 4, and 6.55 minutes. The data is plotted as 475 nm absorbency vs. time (minutes) and the slope of the line is calculated ( ⁇ Abs 475 nm/ min). Values are expressed as the percentage of the respective untreated ethanol control reaction.
  • the data show that the coumarin derived compounds of formulas II and D1 are substantially as effective as 4-ethyl resorcinol, both compounds having good skin lightening effects.
  • the 7-hydroxy-3,4-dihydro-4-methyl coumarin (B1) compound from which the compounds of the present invention may be derived is not very effective in skin lightening, as measured by the mushroom tyrosinase assay.

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Abstract

L'invention concerne des composés dérivés de la coumarine, de formule I, utilisés en tant qu'agents éclaircissant la peau seuls ou combinés à d'autres agents de soin de la peau et associés à un véhicule cosmétique. Dans la formule (I), R1 et/ou R2 représentent hydrogène (H); des groupes alkyle C1-C12, alcényle, acyle, ou hétéroalkyle (de préférence alcoxy) linéaires ou ramifiés, saturés ou insaturés; et R3 représente un groupe alkyle C1-C12, alcényle, cycloalkyle, cycloalcényle ou hétéroalkyle linéaire ou ramifié, cyclique ou acyclique, saturé ou insaturé; R5 représente un atome d'hydrogène (H), ou R4; et R4 représente un groupe alkyle C1-C22, alcényle, cycloalkyle, cycloalcényle, hétéroalkyle, aryle ou hétéroaryle linéaire ou ramifié, cyclique ou acyclique, saturé ou insaturé, contenant ou pas un hétéroatome. Les composés, compositions et procédés de l'invention possèdent des propriétés éclaircissantes pour la peau, peuvent être moins irritants pour la peau, et sont rentables et relativement simples à fabriquer et à mettre en oeuvre. L'invention porte également sur des procédés de fabrication de composés de formule générale I à partir de dérivés de 7-hydroxy coumarine substituée en 4.
EP05715365.2A 2004-02-27 2005-02-16 Procédé de fabrication de composés dérivés de coumarine Active EP1718594B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/789,293 US7300646B2 (en) 2004-02-27 2004-02-27 Skin lightening agents, compositions and methods
PCT/EP2005/001595 WO2005085169A1 (fr) 2004-02-27 2005-02-16 Compositions, procedes et agents eclaircissant la peau

Publications (2)

Publication Number Publication Date
EP1718594A1 true EP1718594A1 (fr) 2006-11-08
EP1718594B1 EP1718594B1 (fr) 2015-06-10

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EP05715365.2A Active EP1718594B1 (fr) 2004-02-27 2005-02-16 Procédé de fabrication de composés dérivés de coumarine

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US (2) US7300646B2 (fr)
EP (1) EP1718594B1 (fr)
JP (1) JP4855382B2 (fr)
AU (1) AU2005219510B2 (fr)
BR (1) BRPI0507222B1 (fr)
ES (1) ES2543980T3 (fr)
NZ (1) NZ549358A (fr)
TW (1) TWI391145B (fr)
WO (1) WO2005085169A1 (fr)
ZA (1) ZA200607017B (fr)

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FR2939136B1 (fr) 2008-12-02 2010-12-03 Galderma Res & Dev Nouveaux composes 4-(heterocycloalkyl)-benzene-1,3-diol comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique
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CA2769512C (fr) 2009-07-29 2019-07-09 Duke University Compositions renfermant des antagonistes du recepteur fp et leur utilisation pour inhiber la croissance des poils
FR2953834B1 (fr) 2009-12-10 2012-01-13 Galderma Res & Dev Nouveaux composes 4-(azacycloalkyl)-benzene-1,3-diol comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique
WO2013009927A2 (fr) 2011-07-11 2013-01-17 Advanced Liquid Logic, Inc. Actionneurs de gouttelettes et techniques pour dosages à base de gouttelettes
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Also Published As

Publication number Publication date
NZ549358A (en) 2010-01-29
US7300646B2 (en) 2007-11-27
AU2005219510A1 (en) 2005-09-15
TW200531706A (en) 2005-10-01
ES2543980T3 (es) 2015-08-26
EP1718594B1 (fr) 2015-06-10
TWI391145B (zh) 2013-04-01
WO2005085169A1 (fr) 2005-09-15
BRPI0507222B1 (pt) 2015-09-08
US7723537B2 (en) 2010-05-25
US20080039636A1 (en) 2008-02-14
BRPI0507222A (pt) 2007-06-19
ZA200607017B (en) 2008-04-30
AU2005219510B2 (en) 2008-05-15
JP4855382B2 (ja) 2012-01-18
JP2007523932A (ja) 2007-08-23
US20050191250A1 (en) 2005-09-01

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